Nitrofurylpyrimidines

ABSTRACT

Compounds of the formula WHEREIN R is saturated or unsaturated, straight-chain or branched hydrocarbon aliphatic group of 1-6 carbon atoms or cyclic alkyl of 3-7 carbon atoms, alkyl of 1-6 carbon atoms wherein 1-2 carbon atoms are substituted by hydroxy or by acyloxy of 1-6 carbon atoms or one carbon atom thereof is substituted by alkoxy of 1-6 carbon atoms, by dialkylamino wherein each alkyl group contains 1-6 carbon atoms, by tetrahydrofuryl or phenyl and R&#39;&#39; is hydrogen or acyl of 1-6 carbon atoms possess systemic antibacterial activity in addition to activity against Trichomonas vaginalis.

Nov. 5, 1974 NITROFURYLPYRIMIDINES Inventors: Rudolf Albrecht;Hans-Joachim Kessler; Eberhard Schriider, all of Berlin, GermanySchering Aktiengesellschaft, Berlin & Bergkamen, Germany Filed: Mar. 16,1972 Appl. No.: 235,426

Assignee:

Foreign Application Priority Data Mar. 17 19 71 Germany 2113529 US.CL... 260/256.4 C, 260/2471 A, 260/2475 R, 260/251, 424/248, 424/251lnt. Cl C07d 51/36 Field of Search 260/2564 C References Cited UNITEDSTATES PATENTS 12/1972 Gutsche et a1. 260/2564 C PrimaryExaminer-Raymond V. Rush Attorney, Agent, or FirmMillen, Raptcs & White[57] ABSTRACT Compounds of the formula I I N /R 0 wherein R is saturatedor unsaturated, straight-chain or branched hydrocarbon aliphatic groupof 1-6 carbon atoms or cyclic alkyl of 3-7 carbon atoms, alkyl Fa ho 191 einl $199! om are substituted by hydroxy or by acyloxy of l-6 carbonatoms or one carbon atom thereof is substituted by alkoxy of l-6 carbonatoms, by dialkylamino wherein each alkyl group contains l-6 carbonatoms, by tetrahydrofuryl or phenyl and R is hydrogen or acyl of l-6carbon atoms possess systemic anti-bacterial activity in addition toactivity against Trichomonas vaginalis.

28 Claims, N0 Drawings BACKGROUND OF THE INVENTION This inventionrelates to novel nitrofurylpyrimidines. U.S. application Ser. No.55,601, filed July, 16, 1.970, now US. Pat. No. 3,707,485, relates tocompounds of the formula SUMMARY OF THE INVENTION The compounds of thisinvention are nitrofurylpyrimidines of the general Formula I wherein Ris saturated or unsaturated, straight-chain or branched aliphatichydrocarbon, e.g., alkyl, or l-6 carbon atoms or cyclic alkyl of 3-7carbon atoms, alkyl of l-6 carbon atoms wherein 1-2 carbon atoms aresubstituted by hydroxy or acyloxy of l-6 carbon atoms or one carbon atomthereof is substituted by alkoxy of l-6 carbon atoms or by dialkylaminowherein each alkyl group contains l-6 carbon atoms, or bytetrahydrofuryl or phenyl and R is hydrogen or acyl of l-6 carbon atoms.

DETAILED DISCUSSION As used herein, alkyl and acyl in each instancecontain l-6 carbon atoms and cyclic alkyl preferably contains 3-7 carbonatoms.

Examples of various classes of compounds of this invention are those ofFormula I wherein:

a. R is H or acetyl;

b/R is alkyl of l-6 carbon'atoms, preferably l-4, in-

cluding methyl, ethyl, propyl, isopropyl, n-butyl & 2- butyl, e.g.,those of(a), and, in addition to alkyl of l-6 carbon atoms, R can alsobe a corresponding unsaturated group, e.g., allyl and ethynyl;

c. R is alkyl as defined in (b) substituted with l-2 of a hydroxy andacyloxy, e.g.,.acetoxy, preferably in the l or 2 position, e;g., thoseof (a);

d. R is alkyl as defined in (b) substituted with dialkylamino, e.g.,dimet'hylamino, methylethylamino, dicthylamino, preferably in the 2position, e.g., those of (a);

e. the compound is in the form of an acid addition salt, e.g.,hemisulfate of hydrochloride including those of (a), (b), (c) and (d).Examples of cycloalkyl are cyclopropyl, cyclopentyl and cyclohexyl.

2 Examples of acyloxy are formyloxy, acetoxy, propionyloxy, butyryloxyand other alkanoyloxy.

Examples of alkoxy are methoxy, ethoxy, propoxy, i-propoxy and n-butoxy.The tetrahydrofuryl substituent is preferably at the 1 -position andpreferably attached by the 2-carbon atom thereof. The phenyl group ispreferably at the 1-position.

The compounds of this invention which are sufficiently basic to formacid addition salts can be in-the form of physiologically acceptableacid addition salts. Thus, this invention embraces compounds of FormulaI both in free base form and in the form of an acid addition salt with aphysiologically compatible acid. Examples of physiologically acceptableacids are hydrochloric acid, sulfuric acid, phosphoric acid, aceticacid, propionic acid, lactic acid, succinic acid, tartaric acid, citricacid, benzoic acid, salicylic acid, nicotinic acid and heptagluconicacid.

Other pharmaceutically acceptable acid addition salts, i.e., of acidswhich do not materially increase the toxicity of the compounds of this vinvention, include salts of other mineral acids, such as, forexample,hydriodic, hydrobromic, metaphospho'ric and .nitric as well as salts oforganic acids, such as, for example, malic, glycolic, gluconic andarylsulfonic, e.g., p-toluenesulfonic acids. H I f The acid additionsalts of this invention are not limited to those formed withpharmaceutically acceptable acids. Other acids, e.g., those formed withperchloric and other toxic and/or unstable acids are useful forisolation, characterization and purification of the free base. Theseacid addition salts can, if desired, thereafter be converted back to thefree base and acid addition salts of pharmeceutically acceptable acids,employing conventional procedures. 1 v

This invention relates both to single compounds of Formula I and tomixtures of one or more thereof.

The compounds of Formula I are produced by reacting a compound of thegeneral Formula II 'ocrr CH-Z o N 2 2 wherein R" is hydrogen or nitro,and Z is a sulfonic acid ester group, a bromine or chlorine, with aprimary amine of the general Formula R-NH (Ill) wherein R has the valuesgiven above; and subsequently hitrating the thus-obtained compoundswherein R" H and, optionally, prior to or after thenitration, acylatingthe amino group and/or any hydroxy groups present and/or saponifying theacylamino group and/or any acyloxy groups present; and optionallyisolating the amino compounds of general Formula I from the reactionproduct in the form of the acid addition salts thereof; or optionallyconverting the free amino compounds of general Formula I, with organicor inorganic acids, into the acid addition salts thereof orliberatingthe free amino compounds of Formula I fromthe acid addition salts withbases.

The compounds according to Formula I can be produced in acid additionsalt form by isolating them directly from the reactions conducted in anacidic medium, e.g., nitration, acidic saponification, for example, inthe form of the hydrochlorides, acid sulfates, or'neutral sulfates, orby preparing them from the free base by subsequent treatment with anacid. Compounds acpounds in concentrated sulfuric acid or aceticanhydride and mixing with concentrated nitric acid or a mixture ofconcentrated nitric acid and concentrated sulfuric acid. In general,this reaction is conducted at a temperature from C. to +40 C.

The acylations are conducted by treating the secondary amino compoundswith an acid anhydride, or reacting same in a basic medium, e.g.,pyridine, with an acid halogenide. The saponification of the acylaminogroup and/or of the acyloxy group is conducted in a conventional manner.v

The novel compounds possess anti-bacteria activity as well as activityagainst Trichomonas vaginalis. The minimum inhibitory concentrations(MIC) of several compounds of Formula I against several pathogenic germsare set forth in Table I. For purposes of comparison, the MIC values ofthe commercially available nitrofurantoin, determined under identicalconditions are ethoxy ]-pyrimidine In contrast to nitrofurantoin which,after oral administration, is detectable in microbiologicallyactive formonly in the urine, the above-mentioned compounds of this invention canalso be detected in the bloodstream. Consequently, thesecompoundsexhibit a systemic effect, not shown by nitrofurantoin, even incase of model infections, e.g., staphylococci, as shown in Table II.

TABLE II The compounds of this invention can be employed in thetreatment of trichomoniasis and in bacterial infections, e.g., staph.infections. They can be administered in forms customarily employed inpharmaceuticals. For oral administration, especially suitable aretablets, dragees, capsules, pills, suspensions and solutions. Suitableexcipients for tablets are, for example, lactose, amylose, talc,gelatin, magnesium stearate, etc.

For topical administration, suitable are powders, solutions,suspensions, aerosols, and vaginal suppositories. For parenteralapplication, aqueous and oily solutions or suspensions can be employed.

The compounds of this invention are formulated so as to provide, forexample, 005 0.5 g. of the effective agent in admixture with 0,1 to 5 g.of a pharmacologically indifferent excipient, e.g., a pharmaceuticallyacceptable carrier, per unit dosage, e.g., per tablet.

The novel effective agents are usually administered in amountsof between0.1 and 4.0 g. per patient per day.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description,

utilize the present invention to its fullest extent. The

following preferred specific embodiments are, therefore, to be construedas merely illustrative, and not li'mitative of the remainder of thedisclosure in any way whatsoever;

EXAMPLE 1 a. 2-(2-Furyl)-5-(2-methylaminoethoxy)-pyrimidine 5.4 g. of2-(2-furyl)-5-(2-toluenesulfonyloxyethoxy)-pyrimidine is refluxed for 18hours in ml. of ethanol and 50 ml. of aqueous methylamine solution (35percent strength). Then, 25 ml. of methylamine solution is again added,and the refluxing continued for 6 hours. Thereafter, the reactionmixture is concentrated, mixed with water, made alkaline with 2N NaOH,and the product is extracted with ethyl acetate. The'ethyl acetatesolution is dried, evaporated, and the residue is recrystallized fromdiisopropyl ether. Yield: 2.2 g. Melting point: C. b. 2-(5-Nitro-2-furyl)-5-(2-methylaminoethoxy)- pyrimidine Hydrochloride 1.0 g. of2-(2-furyl)-5-(2-methylaminoethoxy)- pyramidine is dissolved in 7 ml. ofconcentrated sulfuric acid, cooled to 0 C., and a mixture of 0.4 ml. ofconcentrated nitric acid (s.g. 1.52) and 0.4 ml. of concentratedsulfuric acid is added thereto. The mixture is agitated for 1 hour at 0C. and then for 2 hours at room temperature. Then, the mixture is pouredinto ice water, neutralized with NaOH, saturated with NaCl, and theproduct is extracted with ethyl acetate. The ethyl acetate solution isdried, mixed with ethanolic HCl,

Mic robiologically Active ED (mg/kg.)

Level after Application Staph.aur. of I00 mg./kg. p.o.

Blood Urine Nitrofurantoin 200 2-(5-Nitro-2-furyl)-5-[2-(2-hydroxyethyl' amino)-ethoxy]- 20.1

p rimidine hydrochloride evaporated, and the residue is recrystallizedfrom methanol/ethanol 1:1. Yield: 0.1 g., m.p. 235C. (decomposition).

EXAMPLE 2 a. 2-(2-Furyl)-5-(2-n-propylaminoethoxy)-pyrimidine 18.0 g. of2-(2-furyl)-5-(Z-p-toluenesulfonyloxyethoxy)-pyrimidine and 41 ml. ofn-propylamine are refluxed in 200 ml. of ethanol for 30 hours. Then, themixture is concentrated, mixed with water, made alkaline with 2N NaOH;the product is extracted with ethyl acetate, the ethyl acetate solutionis washed, dried, evaporated, and the residue is recrystallized fromdiisopropyl ether. Yield: 9.3 g., m.p. 74 C.

. b. 2-(5-Nitro-2-furyl)-5-(2-n-propylaminoethoxy)- pyrimidineHydrochloride This compound is produced analogously to Example 1(b) from2.47 g. of 2-(2-furyl)-5-(2-n-propylaminoethoxy)-pyrimidine. The productis recrystallized from ethanol. Yield: 1.7 g., m.p. 217 C.

EXAMPLE 3 ethoxy]-pyrimidine Hydrochloride 12.9 g. of 2-( 2-furyl)-5-[2-(N-acetyl-2- acetoxyethylamino)-ethoxy]-pyrimidine is dissolved in 80ml. of acetic anhydride; at C., a mixture of 4.15 ml. of concentratednitric acid (s.g. 1.52) and 4.15 ml. of concentratedsulfuric acid isadded thereto. The reaction mixture is agitated at 0 C. for 1 hour,poured into ice water, the precipitate is filtered off and refluxed for1 hour with 100 ml. of 5N hydrochloric acid. Thereafter, the mixture isevaporated under vacuum, and the residue is recrystallized frommethanol; yield: 7.1 g., m.p. 214 C.

c. 2-(5-Nitro-2 -furyl)-5-[2-(2-hydroxyethylamino)- ethoxy]-pyrimidineHydrochloride 0.40 of 2-(5-nitro-2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and 0.24 g. ofethanolamine are stirred in 1 ml. of hexamethylphosphoric triamide for 1hour at 60 C. The mixture is mixed with water and a small amount of 1NNaOH and extracted with ethyl acetate. The ethyl acetate solution ismixed withethanolic hydrochloric acid, evaporated, and the residue isrecrystallized from methanol. Yield: 0.9 g.

EXAMPLE 4 2-(5-Nitro-2-furyl)-5[2-(N-acetyl-2acetoxyethylamino)-ethoxy]-pyrimidine 1.25 g, of2-(2-furyl)-5-[2-(N-acetyl-2- acetoxyethylamino)-ethoxy]-pyrimidine isdissolved in 8 ml. of acetic anhydride; under ice cooling, 0.9 ml. ofconcentrated sulfuric acid and 0.45 ml. of concentrated nitric acid(s.g. 1.48) is gradually added dropwise and the mixture is stirred for 1hour under continued cooling. The reaction mixture is poured on ice,neutralized with NaOH, and the solid product is filtered off andrecrystallized from ethanol. Yield: 0.9 g., m.p. 139-141 C.

EXAMPLE 5 a. 2-(2-Furyl)-5-[2-(N-acetyl-l-acetoxy-2-n-butylamino)-ethoxy]-pyrimidine 36.0 g. of2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and 44.5 g. of2-amino-l-n-butanol are reacted analogously toExample 3(a). Theuncrystallized oily crude product (60 g.) is further processed as such.b. 2-(5-Nitro-2-furyl)-5-[ 2-( l-hydroxy-2-n-butylamino)-ethoxy]-pyrimidine Hydrochloride 49.0 g. of2-(2-furyl)-5-[2-( l-acetoxy-N-acetyl-Z-n-butylamino)-ethoxy]-pyrimidine is reacted analogously to Example3(b). The product is recrystallized from ethanol. Yield: 19.0 g., m.p.147 C. c.2-(5-Nitro-2-furyl)-5-[2-(1-hydroxy-2-nbutylamino)-ethoxy]-pyrimidine19.0 g. of 2-(5-nitro-2-furyl)-5-[2-(1-hydroxy-2-n-butylamino)-ethoxy]-pyrimidine hydrochloride is dissolved inwater; NaHCO is added thereto and the mixture is agitated for one-halfhour; then, the solid product is filtered off and recrystallized fromethanol. Yield: 2.7 g., m.p. 114 C.

EXAMPLE 62-(5-Nitro-2-furyl)-5-[2-N-acetyl-1-acetoxy-2-nbutylamino)-ethoxy]-pyramidine49.0 g. of 2-(2-furyl)-5-[2-(N-acetyl-.l-acetoxy-2-n-butylamino)-ethoxy]-pyrimidine is reacted analogously to Example 4.The product is recrystallized from methanol. Yield: 21.0 g., m.p. 72 C.

EXAMPLE 7 2-(5-Nitro-2-furyl)-5-[2-(2-methoxyethylamino)-ethoxy]-pyrimidine Hydrochloride 10.0 g. of2-(5-nitro-2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine isrefluxed with 5.6 g. of 2-methoxyethylamine in '80 ml. of dioxanefor 5hours, then concentrated, mixed with water, made alkaline with NaOH, andextracted with ethyl acetate. The ethyl acetate solution is dried, mixedwith ethanolic HCl, concentrated by evaporation, and the residue isrecrystallized from methanol. Yield: 1.8 g., m.p. 190 C.

EXAMPLE 8 2-( 5-Nitro-2-fury1)-5- 2-( 3 methoxy-n-propylaminoethoxy]-pyrimidine Hydrochloride 4.0 g. of2-(5-nitro-2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine isrefluxed with 2.7 g. of 3-methoxy-n-propylamine in 20 ml. of dioxane for6 hours. The mixture is mixed with water, made alkaline with NaOH, andextracted with ethyl acetate. The ethyl acetate solution is dried,evaporated, and the residue (about 4 g.) is chromatographed on g. ofsilica gel with methanol/chloroform 1:1. The fractions with R; 0.37(thin-layer chromatography on silica gel, same mobile phase system) arecombined, mixed with ethanolic HCl, evaporated, and the residue isrecrystallized from isopropanol. Yield: 0.3 g., m.p. 186 C.

EXAMPLE 9 a.2-(2-Furyl)-5-[2-(N-acetyl-Z-dimethylaminoethylamino)-ethoxy]-pyrimidine18.0 g. of 2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and33.0 g. of 2-dimethylaminoethylamine are refluxed in 150 ml. of ethanolfor 48 hours. The mixture is then poured into water, made alkaline,taken up in ethyl acetate, and evaporated. The residue is dissolved in50 ml. of acetic anhydride, mixed with several drops of concentrated HSO heated for 15 minutes to 100 C., and evaporated under vacuum. Theresidue is recrystallized from toluene. Yield: 14.9 g., m.p. 112 C. b.2-(5-Nitro-2-furyl)-5-[2-(2- dimethylaminoethylamino)-ethoxy]-pyrimidineDihydrochloride 5.1 g. of2-(2-furyl)-5-[2-N-acetyl-2-dimethylaminoethylamino)-ethoxy]-pyrimidineis nitrated and saponified analogously to Example 3(b). The product isrecrystallized from methanol. Yield: 0.9 g., m.p. 2 l-2l 8 C.(decomposition).

EXAMPLE l02-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2-dimethylaminoethylamino)-ethoxy]-pyrimidineHydrogen Sulfate 5.9 g. of 2-(2-furyl)-5-[2-(N-acetyl-2-dimethylaminoethylamino)-ethoxy]'-pyrimidine is mixed in 40 ml. ofacetic anhydride with 2.1 ml. of concentrated nitric acid (s.g. 1.48)and 2.1 ml. of concen: trated sulfuric acid at 0 C.; the mixture isagitated for 1 hour, poured into ice water, and neutralized with NaOH.The product which crystallizes upon ice cooling is filtered off andrecrystallized from ethanol in the presence of 2.0 ml. of sulfuric acid.Yield: 2.6 g., m.p. 170 C. (decomposition).

EXAMPLE 1 l a. 2-(2-Furyl)-5-[2-(N-acetyl-2-diethylaminoethylamino)-ethoxy]-pyrimidine The compound is producedanalogously to Example 9(a) from 3.6 g. of2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 5.8 g. of2-diethylaminoethylamine. The uncrystallizable crude product (2.9 g.) isfurther processed as such. b.2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2-diethylaminoethylamino)-ethoxy]-pyrimidineThe compound is prepared analogously to Example 10 from 2.9 g. of2-(2-furyl)-5-[2-(N-acetyl-2-diethylaminoethylamino)-ethoxy]-pyrimidine,but the crude product is recrystallized from ethanol without addingsulfuric acid. Yield: 1.9 g., m.p. l4ll43 C.

EXAMPLE 12 a.2-(5-Nitro-2-furyl)-5-[2-(2-diethylaminoethylamino)-ethoxy]-pyrimidineDihydrochloride 1.9 g. of 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2-diethylaminoethylamino)-ethoxy]-pyrimidine is refluxed in ml. of 5Nl-lCl for l 178 hours. The reaction mixture is completely evaporatedunder vacuum, and the residue is recrystallized from ethanol. Yield:0.98 g., m.p. l86187 C. b.2-(5-Nitro-2-furyl)-5-[2-(2-diethylaminoethylamino)-ethoxy]-pyrimidineDihydrochloride 12.2 of 2-(5-Nitro-2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidineand 7.0 g. ofZ-diethylaminoethylamine are refluxed in 60 ml. of dioxane for 4 hours.Then, the mixture is mixed with water, taken up in ethyl acetate, andthe ethyl acetate solution is dried, mixed withethanolic HCl, evaporatedand the residue recrystallized from ethanol. Yield: 2.6

EXAMPLE 13 2-(5-Nitro-2-furyl)-5-[2-(tetrahydro-2-furylmethylamino)-ethoxy]-pyrimidine Hydrochloride 0.81 g. of 2-(5-nitro-2-furyl)-5-( 2-ptoluenesulfonyloxyethoxy)-pyrimidine and 0.4 g.of tetrahydrofurfurylamine are refluxed in 20 ml. of dioxane for 4hours. Thereafter, the reaction mixture is concentrated, taken up inwater, extracted with ethyl acetate, the ethyl acetate solution isdried, mixed with ethanolic HCl, evaporated, and the residuerecrystallized from ethanol. Yield: 0.30 g., m.p. 232 C.

EXAMPLE l4 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-methylamino)-ethoxy]-pyrimidine 3.5 g. of 2-(2-furyl)-5-(2-methylaminoethoxy)-pyrimidine is heated to 100 C. for one-half hour in 50 ml. of aceticanhydride; then, the mixture is cooled to 05 C. and 1.65 ml. ofconcentrated nitric acid (s.g. 1.52) and 1.65 ml. of concentratedsulfuric acid are I added thereto. The reaction mixture is agitated foranpyrimidine 5.4 g. of2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and 15 ml. ofethylamine are refluxed in ml. of ethanol for 20 hours. Then, themixture is concentrated, mixed with water, made alkaline ith 2N NaOl-l,the product is extracted with ethyl acetate, the ethyl acetate solutionis washed, dried, and evaporated. The residue is mixed with 40 ml. ofaetic anhydride and 2 drops of concentrated sulfuric acid, and thenheated for 1 hour to C. The mixture is then evaporated under vacuum, theresidue mixed with water, made alkaline with 2N NaOH, extracted withethyl acetate, the ethyl acetate solution is evaporated, the residue isrecrystallized from diisopropyl ether/tetrahydrofuran 2:1. Yield: 3.3g., m.p. 133 C.

b. 2-(5-Nitro-2-furyl) 5-[Z-(N-acetyl-ethylamino)- ethoxy]-pyrimidine3,3 g. of 2-(2-furyl)-5-[2-(N-acetyl-ethylamino)- ethoxy]-pyrimidine isdissolved in 20 ml. of acetic anhydride and, at 05 C., a mixture of 1.3ml. of concentrated nitric acid (s.g. 1.48) and 1.3 ml. of concentratedsulfuric acid is added dropwise thereto. Then, the mixture is agitatedunder ice cooling for 1 hour, poured into ice water, the productextracted with ethyl acetate, and the ethyl acetate solution is washed,dried, evaporated, and the residue recrystallized from ethanol. Yield:2.0 g., m.p. 142 C.

EXAMPLE 16 a. 2-(2-Fury1)-5-[2-(N-acetyl-n-propylamino)-ethoxy]-pyrimidine This compound is produced analogously to Example 15(a) from10.8 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and17.7 g. of n-propylamine. The product is recrystallized from ethylacetate/diisopropyl ether 1:2. Yield: 6.2 g., m.p. 116 C b.2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-n-propylamino)- ethoxy]-pyrimidineThe compound is prepared in analogy to Example 15(b) from 6.2 g. of2-(2-furyl)-5-(N-acetyl-npropylamino)-ethoxy]-pyrimidine. The product isrecrystallized from ethanol. Yield: 2.9 g., m.p. 128 C.

EXAMPLE 17 a. 2-(2-Furyl)-5-[2-(N-acetyl-isopropylamino)-ethoxy]-pyrimidine This compound is prepared analogously to Example15(a) from 5.4 g. of2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 4.43 g. ofisopropylamine. The product is recrystallized from diisopropyl ether.Yield: 2.9 g., m.p. 100 C.

b. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-isopropylamino)-ethoxyl-pyrimidine The compound is produced analogously to Example 15(b)from 2.9 g. of2-(2-furyl)-5-[2-(N-acetylisopropylamino)-ethoxy]-pyrimidine. Theproduct is recrystallized from ethanol. Yield: 2.0 g., m.p. 166 C.

EXAMPLE 18 EXAMPLE 10 a.2-(2-Furyl)-5-[2-(N-acetyl-Z-butylamino)-ethoxy]- pyrimidine 19 Thiscompound is prepared in analogy to Example 15(a) from 3.60 g. of2-(2-furyl)-5,-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 3.65 g. of2-butylamine. The product is recrystallized from toluene. Yield: 2.1 g.,m.p. 100-101 C. b. 2-(5-Nitro-2 -furyl)--[2-(N-acetyl-2-butylamino)-ethoxy]-pyrimidine This compound is prepared analogously to Example15(b) from 2.1 g. of 2-(2-furyl)-5-[2-(N-acetyl-2-butylamino)-ethoxy]-pyrimidine. The product is re crystallized fromethanol. Yield: 1.5 g., m.p. 137-l39 C.

EXAMPLE 20 a. 2-(2-Furyl)-5-[2-(N-acetyl-cyclopentylamino)-ethoxyI-pyrimidine The compound is prepared analogously to Example 15(a)from 3.6 g. of 2-(2-furyl) 5-(2-ptoluenesulfonyloxyethoxy)-pyrimidineand 4.25 g. of cyclopentylamine. The product is recrystallized fromtoluene. Yield: 2.73 g., m.p. ll0-1 1 1 C.

b. 2-(5-Nitro-2-furyl)-5-[Z-(N-acetylcyclopentylamino)-ethoxy]-pyrimidine The compound is prepared in analogy to Example 7 (b)from 2.45 g. of 2-(2-fury1)-5-[2-(N-acety1- 15(b) ,from 1.20 g.

cyclopentylamino)-ethoxy]-pyrimidine. The product is recrystallized fromethanol. Yield: 0.82 g., m.p. 139 C.

EXAMPLE 21 a. 2-(2-Furyl)-5-[2-(N-acetyl-cyclohexylamino)-ethoxyl-pyrimidine This compound is produced according to Example 15(a)from 3.6 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidineand 9.9 g. of cyclohexylamine. The product is recrystallized fromtoluene. Yield: 2.1 g., m.p. 136137 C.

b. 2-(5-Nitro-2-furyl)-5-(N-acetyl-cyclohexylamino)- ethoxy]-pyrimidineThe compound is prepared analogously to Example 15(b) from 2.05 g. of2-(2-furyl)-5-[2-(N-acetylcyclohexylamino)- ethoxy[-pyrimidine. Theproduct is recrystallized from ethanol. Yield: 1.25 g., m.p. 143144 C.

EXAMPLE 22 b. 2-(2-Furyl)-5-[2-(N-acetyl-2-methoxyethylamino)-ethoxyl-pyrimidine This compound is prepared analogously to Example15(a) from 27.0 g. of2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 28.2 g. of2-methoxyethylamine. The product is recrystallized from diisopropylether/tetrahydrofuran. 2:1. Yield: 15.2 g., m.p. 113 C. b.2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2-methoxyethylamino)-ethoxy]-pyrimidine This compound is producedanalogously to Example 15(b) from 15.2 g. of2-(2-furyl)-5-[2-(N-acetyl-2- methoxyethylamino)-ethoxy]-pyrimidine. Theproduct is recrystallized from ethanol. Yield: 8.8 g., m.p. 1 18C.

EXAMPLE 23 a. 2-(2-Furyl)-5-[2-(N-acetyl-benzylamino)-ethoxy]-pyrimidine This compound is prepared analogously to Example 15(a) from2.52 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and3.75 g. of benzylamine. The product is further processed as the crudeproduct. Yield: 1.30 g., m.p. 107-109 C.2-(5-Nitro-2furyl)-5-[Z-(N-acetyl-benzylamino)- ethoxy]-pyrimidine Thecompound is prepared in analogy to Example of2-(2-furyl)-5-(N-acetylbenzylamino)-ethoxy]-pyrimidine. The product isrecrystallized from isopropanol. Yield: 0.36 g., m.p. 131-134 C.

EXAMPLE 24 a. 2-(2-Furyl)-5-(N-formyl-2-n-propylaminoethoxy)- pyrimidine2.47 g. of 2-(2-furyl)-5-(2-n-propylaminoethoxy)- pyrimidine isdissolved in 20 ml. of formic acid and 6 ml. of acetic anhydride andallowed to stand overnight. The reaction mixture is completelyevaporated under vacuum, and the residue is recrystallized fromdiisopropyl ether. Yield: 1.70 g., m.p. 98 C.

b. 2-(5-Nitro-2-furyl)-5-(N-formyl-2-n-propylaminoethoxy)-pyrimidine0.27 g. of 2-(2-furyl)-5-(N-formyl-2-n-propylaminoethoxy)-pyrimidine isdissolved in 5 ml. of acetic anhydride, mixed at C. with 0.1 ml. ofconcentrated sulfuric acid and 0.1 ml. of concentrated nitric acid,agitated at this temperature for 1 hour, poured into ice water, and thesolid product isrecrystallized from isopropanol.

Yield: 0.1 g., m.p. 132 C.

EXAMPLE 25 a. 2-(2-Furyl)-5-[2-(N-n-butyryl-n-propylamino)-ethoxy]-pyrimidine 1.20 g. of 2-(2-furyl)-5-(2-n-propylaminoethoxy)-pyrimidine is dissolved in 20 ml. of pyridine; 0.51 ml. of n-butyrylchloride is added and the mixture is agitated at room temperature for 1hour, then poured into water, acidified with hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate solution is dried,concentrated, and recrystallized from ethanol.

Yield: 0.50 g., m.p. 110 C. I b.2-(5-Nitro-2-furyl)-5-[2-(N-n-butyryl-npropylamino)-ethoxy]-pyrimidineThe compound is prepared analogously to Example 24(b) from 0.3 g. of2-(2-furyl)-5-[Z-(N-n-butyryl-npropylamino)-ethoxy]-pyrimidine. Theproduct is recrystallized from isopropanol. Yield: 0.15 g., m.p. 90 C.

EXAMPLE 26 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2-hydroxyethylamino)-ethoxy]-pyrimidine 3.78 g. of2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2-acetoxyethylamino)-ethoxy]-pyrimidine is agitated in 200 ml. of 1N HClfor 12 hours at 40 C.; then, the reaction mixture is completelyevaporated under vacuum and the residue recrystallized from methanol.Yield: 1.1 g., m.p. 179 C.

EXAMPLE 27 2-(5-Nitro-2-furyl)-5-(2-cyclohexylaminoethoxy)- pyrimidineHydrochloride 2.0 of2-(5-nitro-2-furyl)-5-('2-ptoluenesulfonyloxyethoxy)-pyrimidine isagitated in ml. of hcxamethylphosphoric triumide with 1.7 g. ofcyclohexylamine for 2 hours at 60 C. The reaction mixture is mixed withwater, the thus-precipitated solid product is filtered off, washed withwater, dissolved in ethanolic hydrochloric acid, briefly heated,evaporated to dryness, and the residue is recrystallized from methanol.Yield: 1.0 g., m.p. 250 C. (decomposition).

EXAMPLE 28 2-(5-Nitro-2-furyl)-5-(2-cyclopentylaminoethoxy)- pyrimidineHydrochloride This compound is produced analogously to Example 27 withcyclopentylamine. Yield: 0.3 g., m.p. 238 C. (decomposition).

EXAMPLE 29 a. 2-(2-Furyl)-5-[2-(2-hydroxypropylamino)-ethoxy]-pyrimidine 18.2 g. of2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine is refluxed with18.8 g. of 2- hydroxypropylamine in 200 ml. of ethanol for hours. Themixture is concentrated, mixed with .water and 1N NaOH, extracted withethyl acetate, and the ethyl acetate solution is evaporated. The residueis recrystallized from diisopropyl ether. Yield: 9.3 g., m.p. 100 C. b.2-(2-Furyl)-5-[2-(N-acetyl-Z-acetoxypropylamino)- ethoxy]-pyrimidine 9.3g. of 2(2-furyl)-5-[2-(2-hydroxypropylamino)- ethoxy]-pyrimidine isdissolved in 100 ml. of acetic anhydride and mixed with 1 drop ofconcentrated sulfuric acid. The mixture is allowed to stand for 12 hoursat room temperature and then heated for 1 hour on a steam bath,whereafter it is concentrated, and the product is purified bychromatographing on 300 g. of silica gel in methylene chloride/acetone1:1 and then recrystallized from ethyl acetate. Yield: 6.7 g., m.p. 121C.

c. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2acetoxypropylamino)-ethoxy]-pyrimidine 5.8 g. of2-(2-furyl)-5-[2-(N-acetyl-2- acetoxypropylamino)-ethoxy]-pyrimidine isdissolved in 80 ml. of acetic anhydride and mixed, at 0 C., with 2.6 g.of concentrated nitric acid (s.g. 1.52) and 1.75 ml. of concentratedsulfuric acid. The mixture is agitated for 1 hour at 0 C., poured intoice water, brought to a pH of 4.5- with NaOH, and the thus-precipitatedmaterial is filtered off and recrystallized from ethanol. Yield: 3.9 g.,m.p. 123 C.

EXAMPLE 30 2-(5-Nitr0-2-furyl)-5-[2-(2-hydroxypropylamino)-ethoxy]-pyrimidine Hydrochloride 1.96 g. of2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2-acetoxypropylamino)-ethoxy]-pyrimidine is refluxed in 20 ml. of 5N HClfor 1 hour. The mixture is completely evaporated, and the residue isrecrystallized from methanol. Yield: 1.3 g., m.p. 208 C.

EXAMPLE 31 a. 2-(2-Furyl)-5-[2-(2,3-dihydroxypropylamino)-ethoxy]-pyrimidine 51.0 g. of2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine is refluxed with77.9 g. of l-amino- 2,3-propanediol in 500 ml. of ethanol for 7 hours.The mixture is concentrated, mixed with water and NaOH, and extractedwith ethyl acetate. The ethyl acetate solution is evaporated and theresidue chromatographed on 300 g. of silica gel with methanol/chloroform1:1 and thereafter recrystallized from ethyl acetate. Yield: 6.8 g.,m.p. 94 C. b. 2-(2-Furyl)-5-[2-(N-acetyl-2,3-diacetoxypropylamino)-ethoxy]-pyrimidine 6 g. of2-(2-furyl)-5-[2-(2,3-dihydroxypropylamino)-ethoxy]-pyrimidine is heatedon a steam bath for 2 hours in 120 ml. of acetic anhydride in thepresence of 1 drop of concentrated H SO Then, the mixture is completelyevaporated, and the residue is chromatographed on 250 g. of silica gelwith methanol/chloroform 1:2, and the product is thereafterrecrystallized from methanol. Yield: 3.9 g., m.p. 108 C. c.2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2,3-diacetoxypropylamino)-ethoxy]-pyrimidine 1. v g. of2-(2-furyl)-5-[2-(N-acetyl-2,3- diacetoxypropylamino)-ethoxy]-pyrimidineis dissolved in 20 ml. of acetic anhydride and, at 0 C., a mixture of0.41 ml. of concentrated HNO (s.g. 1.52) and 0.41 ml. of concentrated His added dropwise thereto. The mixture is agitated at 0 C. for 1 hour,

EXAMPLE 32 2-(5-Nitro-2-furyl)-5-[2-(2,3-dihydroxypropylamino)-ethoxy.]-pyrimidine Hydrochloride 1.8 g. of2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2,3-diacctoxypropylamino)-cthoxyl-pyrimidine is refluxed in 20 ml. of 2N HCIfor 1 hour. The mixture is evaporated to dryness and the residuerecrystallized from ethanol. Yield: 1.1 g., m.p. 192 C.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

l. A compound of the formula wherein R is alkyl of 1 -6 carbon atoms,cycloalkyl of 3-7 carbon atoms, alkyl of 1-6 carbon atoms wherein 1-2carbon atoms thereof are substituted by hydroxy or by alkanoyloxy of l-6carbon atoms or 1 carbon atom thereof is substituted by alkoxy of l-6carbon atoms or by dialkylamino wherein each alkyl group contains 1-6carbon atoms or by tetrahydrofuryl or phenyl, and R is alkanoyl of l-6carbon atoms and the physiologically acceptable acid addition saltsthereof.

2. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2-acetoxyethylamino)-ethoxy]-pyrimidine.

3. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- -acetyll acemy: irbutyi am'm'a enian 7 pyrimidine.

4. A compound of claim 1, 2-(5-nitro-2-furyl)=5-[2-(N-acetyl-2-dimethylaminoethyl-amino )-ethoxy pyrimidine hydrogensulfate.

5. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-Z-diethylaminoethylamino)-ethoxy]- pyrimidine.

6. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-methylamino)-ethoxy]-pyrirnidine.

7. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-ethylamino)-ethoxy]-pyrimidine.

8. A compound of claim 1, 2-(5-nitro-2-furyl) -[2-(N-acetyl-n-propylamino)-ethoxy]-pyrimidine.

9. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-isopropylamino)-ethoxy]-pyrimidine.

10. A compound of claim 1, 2-(5-nitro-2-furyl)-5 [2-(N-acetyl-n-butylamino)-ethoxy]-pyrimidine.

11. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-Z-butylamino)-ethoxyl-pyrimidine.

12. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-cyclopentylamino)-ethoxy]-pyrimidine.

13. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-cyclohexylamino )-ethoxy]-pyrimidine.

14. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2-methoxyethylamino)-ethoxy]-pyrimidine.

15. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-benzylamino)-ethoxy]-pyrimidine.

16. A compound of claim 1,2-(5-nitro-2-furyl)-5-(nformyl-2-n-propylaminoethoxy)-pyrimidine.

17. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-n-butyrl-n-ropylamino)-ethoxy]-pyrimidine.

18. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2-hydroxy-ethylamino)-ethoxy]-pyrimidine.

19. A compound of claim 21, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2-acetoxy-propylamino)-ethoxyl-pyrimidine.

20. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2,3-diacetoxy-propylamino)-ethoxy]- pyrimidine.

21. A compound of the formula wherein R is cycloalkyl of 3-7 carbonatoms and the physiologically acceptable acid addition salts thereof.

22. A compound of claim 21, 2-(5-nitro-2-furyI)-5-(2-cyclohexylaminoethoxy)-pyrimidine hydrochloride.

23. A compound of claim 21, 2-(5-nitro-2-furyl)-5-(2-cyclopentylaminoethoxy)-pyrimidine hydrochloride.

24. A compound of the formula wherein R is alkyl of 1-6 carbon atomssubstituted by tetrahydrofuryl and the physiologically acceptable acidaddition salts thereof.

28. A compound of claim 27, 2-(5-nitro-2-furyll-5- :[2 (tetrahydro 2-furylmethylamino) -ethoxy]-pyrimidis? hy o hl

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-acetoxyethylamino)-ethoxy)-pyrimidine.3. A compound of claim 1,2-(5-nitro-2-furyL)-5-(2-(N-acetyl-1-acetoxy-2-n-butyl-amino)-ethoxy)-pyrimidine.
 4. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-dimethylaminoethyl-amino)-ethoxy)-pyrimidine hydrogen sulfate.
 5. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-diethylaminoethylamino)-ethoxy)-pyrimidine.
 6. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-methylamino)-ethoxy)-pyrimidine.
 7. Acompound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-ethylamino)-ethoxy)-pyrimidine.
 8. Acompound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-n-propylamino)-ethoxy)-pyrimidine. 9.A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-isopropylamino)-ethoxy)-pyrimidine.10. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-n-butylamino)-ethoxy)-pyrimidine. 11.A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-butylamino)-ethoxy)-pyrimidine. 12.A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-cyclopentylamino)-ethoxy)-pyrimidine.13. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-cyclohexylamino )-ethoxy)-pyrimidine.14. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-methoxyethylamino)-ethoxy)-pyrimidine.15. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-benzylamino)-ethoxy)-pyrimidine. 16.A compound of claim 1,2-(5-nitro-2-furyl)-5-(n-formyl-2-n-propylaminoethoxy)-pyrimidine.
 17. Acompound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-n-butyrl-n-ropylamino)-ethoxy)-pyrimidine.18. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-hydroxy-ethylamino)-ethoxy)-pyrimidine.19. A compound of claim 11,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-acetoxy-propylamino)-ethoxy)-pyrimidine.
 20. A compound of claim 1,2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2,3-diacetoxy-propylamino)-ethoxy)-pyrimidine.
 21. A compound of theformula
 22. A compound of claim 21,2-(5-nitro-2-furyl)-5-(2-cyclohexylaminoethoxy)-pyrimidinehydrochloride.
 23. A compound of claim 21,2-(5-nitro-2-furyl)-5-(2-cyclopentylaminoethoxy)-pyrimidinehydrochloride.
 24. A compound of the formula
 25. A compound of claim 24,2-(5-nitro-2-furyl)-5-(2-(2-dimethylaminoethylamino)-ethoxy)-pyrimidinedihydrochloride.
 26. A compound of claim 24,2-(5-nitro-2-furyl)-5-(2-(2-diethylaminoethylamino)-ethoxy)-pyrimidinedihydrochloride.
 27. A compound of the formula
 28. A compound of claim27,2-(5-nitro-2-furyl)-5-(2-(tetrahydro-2-furylmethylamino)-ethoxy)-pyrimidinehydrochloride.